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Review
. 2014 Dec;25(12):2689-701.
doi: 10.1681/ASN.2014030262. Epub 2014 Jun 12.

Regulated cell death in AKI

Andreas Linkermann  1 , Guochun Chen  2 , Guie Dong  3 , Ulrich Kunzendorf  4 , Stefan Krautwald  4 , Zheng Dong  5
Affiliations
Review

Regulated cell death in AKI

Andreas Linkermann et al. J Am Soc Nephrol. 2014 Dec.

Abstract

AKI is pathologically characterized by sublethal and lethal damage of renal tubules. Under these conditions, renal tubular cell death may occur by regulated necrosis (RN) or apoptosis. In the last two decades, tubular apoptosis has been shown in preclinical models and some clinical samples from patients with AKI. Mechanistically, apoptotic cell death in AKI may result from well described extrinsic and intrinsic pathways as well as ER stress. Central converging nodes of these pathways are mitochondria, which become fragmented and sensitized to membrane permeabilization in response to cellular stress, resulting in the release of cell death-inducing factors. Whereas apoptosis is known to be regulated, tubular necrosis was thought to occur by accident until recent work unveiled several RN subroutines, most prominently receptor-interacting protein kinase-dependent necroptosis and RN induced by mitochondrial permeability transition. Additionally, other cell death pathways, like pyroptosis and ferroptosis, may also be of pathophysiologic relevance in AKI. Combination therapy targeting multiple cell-death pathways may, therefore, provide maximal therapeutic benefits.

Keywords: acute renal failure; apoptosis; renal injury.

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Figures

Figure 1.
Figure 1.
Pathways of apoptosis. In the intrinsic apoptotic pathway, cellular stress leads to the oligomerization of Bax and Bak, an event that permeabilizes the mitochondrial outer membrane, resulting in the release of apoptogenic factors, including cytochrome c (Cyt.c). In the cytosol, Cyt.c binds Apaf-1 to recruit and activate caspase 9, which further cleaves and activates executioner caspases, such as caspase 3. In the extrinsic apoptotic pathway, ligation of death receptors leads to the recruitment of adapter proteins and subsequent activation of caspase 8, which further activate executioner caspases and prevent necroptosis (Figure 4). Active caspase 8 also cleaves Bid to its truncated form tBid, which translocates to mitochondria to activate the intrinsic pathway to amplify the apoptotic cascade. In the ER stress pathway, caspase 12 mediates the activation of executioner caspases. ER stress may activate the intrinsic apoptotic pathway through Ca2+ signaling and the induction of proapoptotic Bcl-2 family proteins, such as PUMA. IP3R, inositol trisphosphate receptor.
Figure 2.
Figure 2.
Mitochondrial dynamics in apoptosis. Under normal in vivo conditions, Bax and Drp1 are located within the cytosol, whereas Bak is at the mitochondrial outer membrane, where it binds both mitofusin-1 (Mfn1) and mitofusin-2 (Mfn2) to maintain mitochondrial fusion, ensuring its filamentous morphology. On cellular stress, Drp1 translocates to mitochondria, where it forms a restriction ring to activate the cleavage of the organelles; meanwhile, Bak dissociates from Mfn2 to bind Mfn1, which leads to an arrest of fusion and mitochondrial fragmentation. Fragmented mitochondria are more sensitive to Bax oligomerization, resulting in outer membrane permeabilization followed by the release of apoptogenic factors, such as cytochrome c (cyt.c), to activate the intrinsic apoptotic pathway. In addition, mitochondrial fragmentation may also contribute to MPT, leading to necrosis.
Figure 3.
Figure 3.
Necrotic cell death in renal tubular epithelial cells. Four-phase model of necrosis-associated release of DAMPs. (A) Tubular epithelial cell layer under physiologic conditions. (B) On induction of regulated necrosis as the common mechanism of several distinct intracellular signaling pathways, individual cells begin to swell on specific genetically-determined intracellular programs that decode for regulated necrosis (like necroptosis, MPT-mediated regulated necrosis, pyroptosis, or ferroptosis). (C) Severe swelling of the luminal part of a tubular cell that undergoes regulated necrosis. (D) Plasma membrane rupture associated with DAMP release. Regulated necrosis might, therefore, trigger subsequent detrimental immune responses that cause additional organ damage beyond the primary loss of function from cell death. In transplanted organs, a classic setting for IR injury, DAMPs released from necrotic cells might trigger rejection, despite the state of immunosuppression.
Figure 4.
Figure 4.
Model of the integrated molecular signaling pathways of regulated necrosis in renal tubular cells. Four separate pathways of regulated necrosis may contribute to the overall organ damage in AKI. The common downstream mechanism that precedes necrotic cell death is apical swelling, which ultimately induces plasma membrane rupture as recently shown by intravital microscopy. RIPK1/RIPK3-dependent necroptosis has been extensively investigated in the kidney and is triggered by death receptors. RIPK3 is activated by phosphorylation and in turn, phosphorylates the pseudokinase MLKL, which has been suggested to be involved in the opening of plasma membrane calcium channels. Calcium-activated chloride and sodium channels may subsequently open to increase NaCl permeability, which may then cause water influx, cellular volume expansion, and plasma membrane rupture. Ca2+ from this source and others might also be involved in MPT, which directly causes regulated necrosis by unknown means. MPT and necroptosis have been clearly shown to exhibit two separate pathways in AKI. Inhibition of the cell surface cystine/glutamate antiporter system Xc-minus depletes intracellular cystine, which is reduced to cysteine on the intracellular side and together with glycine and glutamate, required for the synthesis of glutathione (GSH). Permanent hydrogen peroxide (H2O2) synthesis, especially in stressed cells, requires the GSH-dependent activity of glutathione peroxidase 4 (GPX4) to prevent H2O2-mediated lipid peroxidation followed by necrotic cell death. Finally, Toll-like receptors (TLRs) are activated by DAMPs or pathogen-associated molecular patterns (PAMPs) and crystals. TLRs activate inflammasomes, which induce caspase 1–dependent maturation of the proinflammatory cytokines IL-1β and IL-18. In parallel, inflammasomes trigger caspase 11–mediated cellular swelling and necrotic cell death, which is referred to as pyroptosis. The combination of DAMP release by necrosis and cytokine maturation renders pyroptosis an even higher immunogenic entity compared with the other pathways of regulated necrosis. Necroptosis can be prevented by the RIPK1 inhibitor Nec-1, its more stable variant, or the human-specific MLKL inhibitor necrosulfonamide (NSA). MPT can be inhibited by cyclosporin (CsA) or sanglifehrin A (SfA), ferroptosis is blocked by the small molecule ferrostatin-1 (Fer-1), and broad spectrum caspase inhibitors (e.g., zVAD-fmk) interfere with pyroptosis signaling. C. rodentium, Citrobacter rodentium; cys, Cysteine; E. coli, Escherichia coli; glu, glutamate; L pneumophila, Legionella pneumophila; V. cholerae, Vibrio cholerae.
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References

    1. Lameire NH, Bagga A, Cruz D, De Maeseneer J, Endre Z, Kellum JA, Liu KD, Mehta RL, Pannu N, Van Biesen W, Vanholder R: Acute kidney injury: An increasing global concern. Lancet 382: 170–179, 2013 - PubMed
    1. Hsu RK, McCulloch CE, Dudley RA, Lo LJ, Hsu CY: Temporal changes in incidence of dialysis-requiring AKI. J Am Soc Nephrol 24: 37–42, 2013 - PMC - PubMed
    1. Hsu CY: Yes, AKI truly leads to CKD. J Am Soc Nephrol 23: 967–969, 2012 - PubMed
    1. Faubel S, Chawla LS, Chertow GM, Goldstein SL, Jaber BL, Liu KD, Acute Kidney Injury Advisory Group of the American Society of Nephrology : Ongoing clinical trials in AKI. Clin J Am Soc Nephrol 7: 861–873, 2012 - PubMed
    1. Bonventre JV, Yang L: Cellular pathophysiology of ischemic acute kidney injury. J Clin Invest 121: 4210–4221, 2011 - PMC - PubMed

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